Failure to achieve a rounded and unobstructed ostia in children who have surgery to repair anomalous coronary arteries can put these children at continued risk for sudden death, but cardiac MRI with virtual angioscopy (VA) before and after the operation can give cardiologists a clear picture of a patient’s risk for sudden death and help direct ongoing management, according to a study in the July issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:205-10).

“Cardiac MRI with virtual angioscopy is an important tool for evaluating anomalous coronary anatomy, myocardial function, and ischemia and should be considered for initial and postoperative assessment of children with anomalous coronary arteries,” lead author Julie A. Brothers, MD, and her coauthors said in reporting their findings.

Anomalous coronary artery is a rare congenital condition in which the left coronary artery (LCA) originates from the right sinus or the right coronary artery (RCA) originates from the left coronary sinus. Dr. Brothers, a pediatric cardiologist, and her colleagues from the Children’s Hospital of Philadelphia and the University of Pennsylvania, also in Philadelphia, studied nine male patients who had operations for anomalous coronary arteries during Feb. 2009-May 2015 in what they said is the first study to document anomalous coronary artery anatomy both before and after surgery. The patients’ average age was 14.1 years; seven had right anomalous coronary arteries and two had left anomalous arteries. After the operations, MRI-VA revealed that two patients still had narrowing in the neo-orifices.

Previous reports recommend surgical repair for all patients with anomalous LCA and for symptomatic patients with anomalous RCA anatomy (Ann Thorac Surg. 2011;92:691-7; Ann Thorac Surg. 2014;98:941-5). MRI-VA allows the surgical team to survey the ostial stenosis before the operation “as if standing within the vessel itself,” Dr. Brothers and her coauthors wrote. Afterward, MRI-VA lets the surgeon and team see if the operation succeeded in repairing the orifices.

In the study population, VA before surgery confirmed elliptical, slit-like orifices in all patients. The operations involved unroofing procedures; two patients also had detachment and resuspension procedures during surgery. After surgery, VA showed that seven patients had round, patent, unobstructed repaired orifices; but two had orifices that were still narrow and somewhat stenotic, Dr. Brothers and her coauthors said. The study group had postoperative MRI-VA an average of 8.6 months after surgery.

“The significance of these findings is unknown; however, if the proposed mechanism of ischemia is due to a slit-like orifice, a continued stenotic orifice may place subjects at risk for sudden death,” the researchers said. The two study patients with the narrowed, stenotic orifices have remained symptom free, with no evidence of ischemia on exercise stress test or cardiac MRI. “These subjects will need to be followed up in the future to monitor for progression or resolution,” the study authors wrote.

Sudden cardiac death (SCD) is more common in anomalous aortic origin of the LCA than the RCA, Dr. Brothers and her colleagues said. Thus, an elliptical, slit-like neo-orifice is a concern because it can become blocked during exercise, possibly leading to lethal ventricular arrhythmia, they said. Ischemia in patients with anomalous coronary artery seems to result from a cumulative effect of exercise.

Patients who undergo the modified unroofing procedure typically have electrocardiography and echocardiography afterward and then get cleared to return to competitive sports in about 3 months if their stress test indicates it. Dr. Brothers and her colleagues said this activity recommendation may need alteration for those patients who have had a heart attack or sudden cardiac arrest, because they may remain at increased risk of SCD after surgery. “At the very least, additional imaging, such as with MRI-VA, should be used in this population,” the study authors said.

While Dr. Brothers and her colleagues acknowledged the small sample size is a limitation of the study, they also pointed out that anomalous coronary artery is a rare disease. They also noted that high-quality VA images can be difficult to obtain in noncompliant patients or those have arrhythmia or irregular breathing. “The images obtained in this study were acquired at an institution very familiar with pediatric cardiac coronary MRI and would be appropriate for assessing the coronary ostia with VA,” they said.

Dr. Brothers and her coauthors had no financial disclosures.

Failure to achieve a rounded and unobstructed ostia in children who have surgery to repair anomalous coronary arteries can put these children at continued risk for sudden death, but cardiac MRI with virtual angioscopy (VA) before and after the operation can give cardiologists a clear picture of a patient’s risk for sudden death and help direct ongoing management, according to a study in the July issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:205-10).

“Cardiac MRI with virtual angioscopy is an important tool for evaluating anomalous coronary anatomy, myocardial function, and ischemia and should be considered for initial and postoperative assessment of children with anomalous coronary arteries,” lead author Julie A. Brothers, MD, and her coauthors said in reporting their findings.

Anomalous coronary artery is a rare congenital condition in which the left coronary artery (LCA) originates from the right sinus or the right coronary artery (RCA) originates from the left coronary sinus. Dr. Brothers, a pediatric cardiologist, and her colleagues from the Children’s Hospital of Philadelphia and the University of Pennsylvania, also in Philadelphia, studied nine male patients who had operations for anomalous coronary arteries during Feb. 2009-May 2015 in what they said is the first study to document anomalous coronary artery anatomy both before and after surgery. The patients’ average age was 14.1 years; seven had right anomalous coronary arteries and two had left anomalous arteries. After the operations, MRI-VA revealed that two patients still had narrowing in the neo-orifices.

Previous reports recommend surgical repair for all patients with anomalous LCA and for symptomatic patients with anomalous RCA anatomy (Ann Thorac Surg. 2011;92:691-7; Ann Thorac Surg. 2014;98:941-5). MRI-VA allows the surgical team to survey the ostial stenosis before the operation “as if standing within the vessel itself,” Dr. Brothers and her coauthors wrote. Afterward, MRI-VA lets the surgeon and team see if the operation succeeded in repairing the orifices.

In the study population, VA before surgery confirmed elliptical, slit-like orifices in all patients. The operations involved unroofing procedures; two patients also had detachment and resuspension procedures during surgery. After surgery, VA showed that seven patients had round, patent, unobstructed repaired orifices; but two had orifices that were still narrow and somewhat stenotic, Dr. Brothers and her coauthors said. The study group had postoperative MRI-VA an average of 8.6 months after surgery.

“The significance of these findings is unknown; however, if the proposed mechanism of ischemia is due to a slit-like orifice, a continued stenotic orifice may place subjects at risk for sudden death,” the researchers said. The two study patients with the narrowed, stenotic orifices have remained symptom free, with no evidence of ischemia on exercise stress test or cardiac MRI. “These subjects will need to be followed up in the future to monitor for progression or resolution,” the study authors wrote.

Sudden cardiac death (SCD) is more common in anomalous aortic origin of the LCA than the RCA, Dr. Brothers and her colleagues said. Thus, an elliptical, slit-like neo-orifice is a concern because it can become blocked during exercise, possibly leading to lethal ventricular arrhythmia, they said. Ischemia in patients with anomalous coronary artery seems to result from a cumulative effect of exercise.

Patients who undergo the modified unroofing procedure typically have electrocardiography and echocardiography afterward and then get cleared to return to competitive sports in about 3 months if their stress test indicates it. Dr. Brothers and her colleagues said this activity recommendation may need alteration for those patients who have had a heart attack or sudden cardiac arrest, because they may remain at increased risk of SCD after surgery. “At the very least, additional imaging, such as with MRI-VA, should be used in this population,” the study authors said.

While Dr. Brothers and her colleagues acknowledged the small sample size is a limitation of the study, they also pointed out that anomalous coronary artery is a rare disease. They also noted that high-quality VA images can be difficult to obtain in noncompliant patients or those have arrhythmia or irregular breathing. “The images obtained in this study were acquired at an institution very familiar with pediatric cardiac coronary MRI and would be appropriate for assessing the coronary ostia with VA,” they said.

Dr. Brothers and her coauthors had no financial disclosures.

Failure to achieve a rounded and unobstructed ostia in children who have surgery to repair anomalous coronary arteries can put these children at continued risk for sudden death, but cardiac MRI with virtual angioscopy (VA) before and after the operation can give cardiologists a clear picture of a patient’s risk for sudden death and help direct ongoing management, according to a study in the July issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:205-10).

“Cardiac MRI with virtual angioscopy is an important tool for evaluating anomalous coronary anatomy, myocardial function, and ischemia and should be considered for initial and postoperative assessment of children with anomalous coronary arteries,” lead author Julie A. Brothers, MD, and her coauthors said in reporting their findings.

Anomalous coronary artery is a rare congenital condition in which the left coronary artery (LCA) originates from the right sinus or the right coronary artery (RCA) originates from the left coronary sinus. Dr. Brothers, a pediatric cardiologist, and her colleagues from the Children’s Hospital of Philadelphia and the University of Pennsylvania, also in Philadelphia, studied nine male patients who had operations for anomalous coronary arteries during Feb. 2009-May 2015 in what they said is the first study to document anomalous coronary artery anatomy both before and after surgery. The patients’ average age was 14.1 years; seven had right anomalous coronary arteries and two had left anomalous arteries. After the operations, MRI-VA revealed that two patients still had narrowing in the neo-orifices.

Previous reports recommend surgical repair for all patients with anomalous LCA and for symptomatic patients with anomalous RCA anatomy (Ann Thorac Surg. 2011;92:691-7; Ann Thorac Surg. 2014;98:941-5). MRI-VA allows the surgical team to survey the ostial stenosis before the operation “as if standing within the vessel itself,” Dr. Brothers and her coauthors wrote. Afterward, MRI-VA lets the surgeon and team see if the operation succeeded in repairing the orifices.

In the study population, VA before surgery confirmed elliptical, slit-like orifices in all patients. The operations involved unroofing procedures; two patients also had detachment and resuspension procedures during surgery. After surgery, VA showed that seven patients had round, patent, unobstructed repaired orifices; but two had orifices that were still narrow and somewhat stenotic, Dr. Brothers and her coauthors said. The study group had postoperative MRI-VA an average of 8.6 months after surgery.

“The significance of these findings is unknown; however, if the proposed mechanism of ischemia is due to a slit-like orifice, a continued stenotic orifice may place subjects at risk for sudden death,” the researchers said. The two study patients with the narrowed, stenotic orifices have remained symptom free, with no evidence of ischemia on exercise stress test or cardiac MRI. “These subjects will need to be followed up in the future to monitor for progression or resolution,” the study authors wrote.

Sudden cardiac death (SCD) is more common in anomalous aortic origin of the LCA than the RCA, Dr. Brothers and her colleagues said. Thus, an elliptical, slit-like neo-orifice is a concern because it can become blocked during exercise, possibly leading to lethal ventricular arrhythmia, they said. Ischemia in patients with anomalous coronary artery seems to result from a cumulative effect of exercise.

Patients who undergo the modified unroofing procedure typically have electrocardiography and echocardiography afterward and then get cleared to return to competitive sports in about 3 months if their stress test indicates it. Dr. Brothers and her colleagues said this activity recommendation may need alteration for those patients who have had a heart attack or sudden cardiac arrest, because they may remain at increased risk of SCD after surgery. “At the very least, additional imaging, such as with MRI-VA, should be used in this population,” the study authors said.

While Dr. Brothers and her colleagues acknowledged the small sample size is a limitation of the study, they also pointed out that anomalous coronary artery is a rare disease. They also noted that high-quality VA images can be difficult to obtain in noncompliant patients or those have arrhythmia or irregular breathing. “The images obtained in this study were acquired at an institution very familiar with pediatric cardiac coronary MRI and would be appropriate for assessing the coronary ostia with VA,” they said.

Dr. Brothers and her coauthors had no financial disclosures.

Traumatic events are extremely common, with as many as 60% of children experiencing some trauma by age 18 years. About 15% of these children will develop posttraumatic stress disorder (PTSD).

Case summary

Jane is a 13-year-old girl who presented because of steadily escalating angry outbursts with her mother, irritable mood, and anxiety since her father went to jail 2 years previously. Prior to the father’s departure from the family, he drank heavily and had been physically violent to Jane’s mother through most of Jane’s life.

Since these events, Jane has been extremely angry and irritable, often fighting extensively with her younger sister. She has severe difficulty separating from her mother, often following her around or demanding to know everything that her mother is doing. Jane herself reports that she feels worried, irritable, and sad much of the time. She is especially angry when thinking about anything related to her father. Jane won’t talk about her father to anyone, except occasionally her mother and one friend. She has difficulty falling asleep and has nightmares. She never thinks about the future, and instead just lives day to day. Images from the past come vividly into her mind. She has highly negative, hopeless views of the world, and doesn’t trust people, so she is unwilling to consider any therapy. Jane’s mother also is highly irritable and snaps at Jane over small things while in the office.

Discussion

The DSM-5 diagnostic criteria for PTSD require that an individual has been exposed to a severe stressor that threatens death, serious injury, or sexual violence through direct experience, witnessing the event happening to others, or learning that the event happened to a close family member or friend. Not all people who experience such events will develop PTSD, however. Additional symptoms are grouped into four areas (rather than three as in the DSM-IV), and a diagnosis requires one or two symptoms in each area:

• Intrusive symptoms including intrusive distressing memories, recurrent dreams with content related to the event, dissociative reactions such as flashbacks, intense distress at exposure to triggers that remind individuals of the event, or marked physiologic reactions to triggers.

• Avoidance of stimuli associated with the event, either memories or thoughts or external reminders.

• Negative cognitions manifesting as changes in thoughts and mood beginning or worsening after the event. These are an inability to remember the event, persistent negative beliefs about oneself or the world, distorted thoughts about the cause or results of the event, persistent negative emotional states such as anger or guilt, decreased participation in activities, feelings of estrangement from others, or an inability to experience positive emotions.

• Changes in arousal and reactivity as shown by irritable behavior, reckless behavior, hypervigilance, an exaggerated startle response, concentration problems, or sleep disturbance.

There are several screening instruments for the presence of a history of traumatic events as well as for symptoms of PTSD. The Child PTSD Symptom Scale (CPSS) is one example of a simple, readily available screening tool. More extensive assessment is an important part of treatment by mental health clinicians.

Treatment

Psychotherapy interventions are the core of treatment for PTSD in young people. Interventions based on cognitive-behavioral therapy (CBT) are the most extensively researched, with trauma-focused CBT (TF-CBT) being the specific intervention with the most research (13 randomized controlled trials showing efficacy) for children and adolescents. There are several other approaches that have evidence of efficacy through randomized controlled trials, and have been specifically studied for different ages, cultural groups, and focus of intervention (group, family, classroom). Child-parent psychotherapy focuses on traumatized 3-to 5-year-olds and works with both parent and child. Eye movement desensitization and preprocessing therapy (EMDR), extensively studied for adults, has some randomized controlled trials in children. The National Child Traumatic Stress Network (NCTSN) has a website listing evidence-based interventions with descriptions of the extent of the evidence for these and other interventions, including the population for which the intervention was designed and information on training and dissemination.

A recent meta-analysis by Morina et al. identified 39 randomized controlled trials with psychological interventions targeting PTSD in children and youth and found a large (0.83) overall effect size vs. wait list control, and a moderate (0.41) effect size vs. an active control such as supportive therapy. There were enough randomized controlled trials to analyze the TF-CBT–based interventions as a group, and these had even larger effect sizes: 1.44 vs. wait list and 0.66 vs. active control. The non-CBT approaches did not have enough studies to be evaluated separately (Clin Psychol Rev. 2016 Jul;47:41-54).

It is important to know which available therapists are trained in specific interventions such as TF-CBT and review the evidence behind other interventions that therapists are using. Advocacy for the training of local therapists, particularly therapists who are affiliated with your practice, can increase these resources.

The evidence for pharmacologic treatment for PTSD in children and adolescents, in contrast to adults, is very thin. In adults, SSRIs have shown a significant benefit, but there have been three randomized controlled trials examining this question in young people with no significant difference shown for the SSRI. One of these compared TF-CBT alone to TF-CBT plus sertraline, with no added benefit for sertraline. A second compared sertraline to placebo and showed no difference, and the third was an extremely brief trial of 1 week of fluoxetine for children with burns, with no effect. There are open label studies of citalopram that have shown some benefit.

Prazosin is an alpha-1 antagonist that decreases the effect of peripheral norepinephrine, which has been shown to decrease reactivity in adults through two randomized controlled trials, but there are case reports in adolescents only. Guanfacine, an alpha-2 agonist that acts centrally to decrease norepinephrine release, has one open label study of the extended-release form in adolescents showing benefit, but there are two negative randomized controlled trials in adults. Other agents such as second-generation antipsychotics and mood stabilizers (specifically carbamazepine and valproic acid) have open label studies in children only and have the potential for significant side effects.

Psychotherapy is clearly the treatment of choice for children and adolescents with PTSD; the difficulty is that avoidance and difficulty trusting people are core symptoms of PTSD, and can lead patients to be extremely reluctant to try therapy. As a pediatrician, you likely already have a trusting relationship with your patient and parent(s), which can provide an opening for discussion.

Psychoeducation about trauma and the specific trauma a child has experienced is a core component and often the first step of PTSD treatment. The NCTSN website provides a goldmine of information about specific types of trauma (found under the tab labeled trauma types), including common symptoms at different developmental stages and specific resources. By providing information to families in a sensitive way, clinicians can help people understand that they are not alone, that their struggles are common reactions to the type of trauma they have experienced, and that people can recover with therapy so that the trauma does not have to go on negatively affecting their lives.

Finally, noting a parent’s possible trauma, and encouraging that parent to get his or her own treatment in order to help the child, can be a crucial first step.

General references

Dr. Hall is assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She said she had no relevant financial disclosures.

Traumatic events are extremely common, with as many as 60% of children experiencing some trauma by age 18 years. About 15% of these children will develop posttraumatic stress disorder (PTSD).

Case summary

Jane is a 13-year-old girl who presented because of steadily escalating angry outbursts with her mother, irritable mood, and anxiety since her father went to jail 2 years previously. Prior to the father’s departure from the family, he drank heavily and had been physically violent to Jane’s mother through most of Jane’s life.

Since these events, Jane has been extremely angry and irritable, often fighting extensively with her younger sister. She has severe difficulty separating from her mother, often following her around or demanding to know everything that her mother is doing. Jane herself reports that she feels worried, irritable, and sad much of the time. She is especially angry when thinking about anything related to her father. Jane won’t talk about her father to anyone, except occasionally her mother and one friend. She has difficulty falling asleep and has nightmares. She never thinks about the future, and instead just lives day to day. Images from the past come vividly into her mind. She has highly negative, hopeless views of the world, and doesn’t trust people, so she is unwilling to consider any therapy. Jane’s mother also is highly irritable and snaps at Jane over small things while in the office.

Discussion

The DSM-5 diagnostic criteria for PTSD require that an individual has been exposed to a severe stressor that threatens death, serious injury, or sexual violence through direct experience, witnessing the event happening to others, or learning that the event happened to a close family member or friend. Not all people who experience such events will develop PTSD, however. Additional symptoms are grouped into four areas (rather than three as in the DSM-IV), and a diagnosis requires one or two symptoms in each area:

• Intrusive symptoms including intrusive distressing memories, recurrent dreams with content related to the event, dissociative reactions such as flashbacks, intense distress at exposure to triggers that remind individuals of the event, or marked physiologic reactions to triggers.

• Avoidance of stimuli associated with the event, either memories or thoughts or external reminders.

• Negative cognitions manifesting as changes in thoughts and mood beginning or worsening after the event. These are an inability to remember the event, persistent negative beliefs about oneself or the world, distorted thoughts about the cause or results of the event, persistent negative emotional states such as anger or guilt, decreased participation in activities, feelings of estrangement from others, or an inability to experience positive emotions.

• Changes in arousal and reactivity as shown by irritable behavior, reckless behavior, hypervigilance, an exaggerated startle response, concentration problems, or sleep disturbance.

There are several screening instruments for the presence of a history of traumatic events as well as for symptoms of PTSD. The Child PTSD Symptom Scale (CPSS) is one example of a simple, readily available screening tool. More extensive assessment is an important part of treatment by mental health clinicians.

Treatment

Psychotherapy interventions are the core of treatment for PTSD in young people. Interventions based on cognitive-behavioral therapy (CBT) are the most extensively researched, with trauma-focused CBT (TF-CBT) being the specific intervention with the most research (13 randomized controlled trials showing efficacy) for children and adolescents. There are several other approaches that have evidence of efficacy through randomized controlled trials, and have been specifically studied for different ages, cultural groups, and focus of intervention (group, family, classroom). Child-parent psychotherapy focuses on traumatized 3-to 5-year-olds and works with both parent and child. Eye movement desensitization and preprocessing therapy (EMDR), extensively studied for adults, has some randomized controlled trials in children. The National Child Traumatic Stress Network (NCTSN) has a website listing evidence-based interventions with descriptions of the extent of the evidence for these and other interventions, including the population for which the intervention was designed and information on training and dissemination.

A recent meta-analysis by Morina et al. identified 39 randomized controlled trials with psychological interventions targeting PTSD in children and youth and found a large (0.83) overall effect size vs. wait list control, and a moderate (0.41) effect size vs. an active control such as supportive therapy. There were enough randomized controlled trials to analyze the TF-CBT–based interventions as a group, and these had even larger effect sizes: 1.44 vs. wait list and 0.66 vs. active control. The non-CBT approaches did not have enough studies to be evaluated separately (Clin Psychol Rev. 2016 Jul;47:41-54).

It is important to know which available therapists are trained in specific interventions such as TF-CBT and review the evidence behind other interventions that therapists are using. Advocacy for the training of local therapists, particularly therapists who are affiliated with your practice, can increase these resources.

The evidence for pharmacologic treatment for PTSD in children and adolescents, in contrast to adults, is very thin. In adults, SSRIs have shown a significant benefit, but there have been three randomized controlled trials examining this question in young people with no significant difference shown for the SSRI. One of these compared TF-CBT alone to TF-CBT plus sertraline, with no added benefit for sertraline. A second compared sertraline to placebo and showed no difference, and the third was an extremely brief trial of 1 week of fluoxetine for children with burns, with no effect. There are open label studies of citalopram that have shown some benefit.

Prazosin is an alpha-1 antagonist that decreases the effect of peripheral norepinephrine, which has been shown to decrease reactivity in adults through two randomized controlled trials, but there are case reports in adolescents only. Guanfacine, an alpha-2 agonist that acts centrally to decrease norepinephrine release, has one open label study of the extended-release form in adolescents showing benefit, but there are two negative randomized controlled trials in adults. Other agents such as second-generation antipsychotics and mood stabilizers (specifically carbamazepine and valproic acid) have open label studies in children only and have the potential for significant side effects.

Psychotherapy is clearly the treatment of choice for children and adolescents with PTSD; the difficulty is that avoidance and difficulty trusting people are core symptoms of PTSD, and can lead patients to be extremely reluctant to try therapy. As a pediatrician, you likely already have a trusting relationship with your patient and parent(s), which can provide an opening for discussion.

Psychoeducation about trauma and the specific trauma a child has experienced is a core component and often the first step of PTSD treatment. The NCTSN website provides a goldmine of information about specific types of trauma (found under the tab labeled trauma types), including common symptoms at different developmental stages and specific resources. By providing information to families in a sensitive way, clinicians can help people understand that they are not alone, that their struggles are common reactions to the type of trauma they have experienced, and that people can recover with therapy so that the trauma does not have to go on negatively affecting their lives.

Finally, noting a parent’s possible trauma, and encouraging that parent to get his or her own treatment in order to help the child, can be a crucial first step.

General references

Dr. Hall is assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She said she had no relevant financial disclosures.

Traumatic events are extremely common, with as many as 60% of children experiencing some trauma by age 18 years. About 15% of these children will develop posttraumatic stress disorder (PTSD).

Case summary

Jane is a 13-year-old girl who presented because of steadily escalating angry outbursts with her mother, irritable mood, and anxiety since her father went to jail 2 years previously. Prior to the father’s departure from the family, he drank heavily and had been physically violent to Jane’s mother through most of Jane’s life.

Since these events, Jane has been extremely angry and irritable, often fighting extensively with her younger sister. She has severe difficulty separating from her mother, often following her around or demanding to know everything that her mother is doing. Jane herself reports that she feels worried, irritable, and sad much of the time. She is especially angry when thinking about anything related to her father. Jane won’t talk about her father to anyone, except occasionally her mother and one friend. She has difficulty falling asleep and has nightmares. She never thinks about the future, and instead just lives day to day. Images from the past come vividly into her mind. She has highly negative, hopeless views of the world, and doesn’t trust people, so she is unwilling to consider any therapy. Jane’s mother also is highly irritable and snaps at Jane over small things while in the office.

Discussion

The DSM-5 diagnostic criteria for PTSD require that an individual has been exposed to a severe stressor that threatens death, serious injury, or sexual violence through direct experience, witnessing the event happening to others, or learning that the event happened to a close family member or friend. Not all people who experience such events will develop PTSD, however. Additional symptoms are grouped into four areas (rather than three as in the DSM-IV), and a diagnosis requires one or two symptoms in each area:

• Intrusive symptoms including intrusive distressing memories, recurrent dreams with content related to the event, dissociative reactions such as flashbacks, intense distress at exposure to triggers that remind individuals of the event, or marked physiologic reactions to triggers.

• Avoidance of stimuli associated with the event, either memories or thoughts or external reminders.

• Negative cognitions manifesting as changes in thoughts and mood beginning or worsening after the event. These are an inability to remember the event, persistent negative beliefs about oneself or the world, distorted thoughts about the cause or results of the event, persistent negative emotional states such as anger or guilt, decreased participation in activities, feelings of estrangement from others, or an inability to experience positive emotions.

• Changes in arousal and reactivity as shown by irritable behavior, reckless behavior, hypervigilance, an exaggerated startle response, concentration problems, or sleep disturbance.

There are several screening instruments for the presence of a history of traumatic events as well as for symptoms of PTSD. The Child PTSD Symptom Scale (CPSS) is one example of a simple, readily available screening tool. More extensive assessment is an important part of treatment by mental health clinicians.

Treatment

Psychotherapy interventions are the core of treatment for PTSD in young people. Interventions based on cognitive-behavioral therapy (CBT) are the most extensively researched, with trauma-focused CBT (TF-CBT) being the specific intervention with the most research (13 randomized controlled trials showing efficacy) for children and adolescents. There are several other approaches that have evidence of efficacy through randomized controlled trials, and have been specifically studied for different ages, cultural groups, and focus of intervention (group, family, classroom). Child-parent psychotherapy focuses on traumatized 3-to 5-year-olds and works with both parent and child. Eye movement desensitization and preprocessing therapy (EMDR), extensively studied for adults, has some randomized controlled trials in children. The National Child Traumatic Stress Network (NCTSN) has a website listing evidence-based interventions with descriptions of the extent of the evidence for these and other interventions, including the population for which the intervention was designed and information on training and dissemination.

A recent meta-analysis by Morina et al. identified 39 randomized controlled trials with psychological interventions targeting PTSD in children and youth and found a large (0.83) overall effect size vs. wait list control, and a moderate (0.41) effect size vs. an active control such as supportive therapy. There were enough randomized controlled trials to analyze the TF-CBT–based interventions as a group, and these had even larger effect sizes: 1.44 vs. wait list and 0.66 vs. active control. The non-CBT approaches did not have enough studies to be evaluated separately (Clin Psychol Rev. 2016 Jul;47:41-54).

It is important to know which available therapists are trained in specific interventions such as TF-CBT and review the evidence behind other interventions that therapists are using. Advocacy for the training of local therapists, particularly therapists who are affiliated with your practice, can increase these resources.

The evidence for pharmacologic treatment for PTSD in children and adolescents, in contrast to adults, is very thin. In adults, SSRIs have shown a significant benefit, but there have been three randomized controlled trials examining this question in young people with no significant difference shown for the SSRI. One of these compared TF-CBT alone to TF-CBT plus sertraline, with no added benefit for sertraline. A second compared sertraline to placebo and showed no difference, and the third was an extremely brief trial of 1 week of fluoxetine for children with burns, with no effect. There are open label studies of citalopram that have shown some benefit.

Prazosin is an alpha-1 antagonist that decreases the effect of peripheral norepinephrine, which has been shown to decrease reactivity in adults through two randomized controlled trials, but there are case reports in adolescents only. Guanfacine, an alpha-2 agonist that acts centrally to decrease norepinephrine release, has one open label study of the extended-release form in adolescents showing benefit, but there are two negative randomized controlled trials in adults. Other agents such as second-generation antipsychotics and mood stabilizers (specifically carbamazepine and valproic acid) have open label studies in children only and have the potential for significant side effects.

Psychotherapy is clearly the treatment of choice for children and adolescents with PTSD; the difficulty is that avoidance and difficulty trusting people are core symptoms of PTSD, and can lead patients to be extremely reluctant to try therapy. As a pediatrician, you likely already have a trusting relationship with your patient and parent(s), which can provide an opening for discussion.

Psychoeducation about trauma and the specific trauma a child has experienced is a core component and often the first step of PTSD treatment. The NCTSN website provides a goldmine of information about specific types of trauma (found under the tab labeled trauma types), including common symptoms at different developmental stages and specific resources. By providing information to families in a sensitive way, clinicians can help people understand that they are not alone, that their struggles are common reactions to the type of trauma they have experienced, and that people can recover with therapy so that the trauma does not have to go on negatively affecting their lives.

Finally, noting a parent’s possible trauma, and encouraging that parent to get his or her own treatment in order to help the child, can be a crucial first step.

General references

Dr. Hall is assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She said she had no relevant financial disclosures.

Theranos Inc founder and CEO Elizabeth Holmes, once touted as the Steve Jobs of biotech for her company's innovative blood-testing technology, has been barred by a U.S. regulator from owning or operating a lab for at least two years.

Dealing the biggest blow yet to the privately held company, the Centers for Medicare & Medicaid Services revoked a key certificate for its California lab and terminated the facility's approval to receive government payments.

Medicare is the government's medical insurance program for the elderly, while Medicaid is for the poor.

The sanctions, which also include an unspecified monetary penalty, come six months after the regulator sent a scathing letter to the company, saying its practices were jeopardizing patient health and safety.

Theranos said late on Thursday that it would continue to service its customers through its Arizona lab.

The company, once valued at $9 billion, was founded by Holmes in 2003 to develop an innovative blood testing device that would give quicker results using just one drop of blood.

However, its fortunes waned after the Wall Street Journal published a series of articles starting in October last year that suggested the devices were flawed and inaccurate.

Forbes magazine said last month that the company's value had fallen to about $800 million, while Holmes' own net worth had shrunk to zero from about $4.5 billion - a figure the magazine had said had made her the richest self-made woman in America.

"Everyone wanted her to succeed," Steve Brozak, president of WBB Securities, told Reuters, noting that the basic blood diagnostics sector has not had a significant advance in technology in 90 years.

Walgreens Boots Alliance terminated its relationship with the company last month and closed operations at all 40 Theranos Wellness Centers at its drug stores in Arizona.

Theranos is also facing a class action lawsuit filed in May accusing it of endangering customer health through "massive failures" that misrepresented test results.

The Palo Alto, California-based company is also being investigated by other federal and state agencies, including the U.S. Securities and Exchange Commission and the State Department of Health in Arizona.

Theranos Inc founder and CEO Elizabeth Holmes, once touted as the Steve Jobs of biotech for her company's innovative blood-testing technology, has been barred by a U.S. regulator from owning or operating a lab for at least two years.

Dealing the biggest blow yet to the privately held company, the Centers for Medicare & Medicaid Services revoked a key certificate for its California lab and terminated the facility's approval to receive government payments.

Medicare is the government's medical insurance program for the elderly, while Medicaid is for the poor.

The sanctions, which also include an unspecified monetary penalty, come six months after the regulator sent a scathing letter to the company, saying its practices were jeopardizing patient health and safety.

Theranos said late on Thursday that it would continue to service its customers through its Arizona lab.

The company, once valued at $9 billion, was founded by Holmes in 2003 to develop an innovative blood testing device that would give quicker results using just one drop of blood.

However, its fortunes waned after the Wall Street Journal published a series of articles starting in October last year that suggested the devices were flawed and inaccurate.

Forbes magazine said last month that the company's value had fallen to about $800 million, while Holmes' own net worth had shrunk to zero from about $4.5 billion - a figure the magazine had said had made her the richest self-made woman in America.

"Everyone wanted her to succeed," Steve Brozak, president of WBB Securities, told Reuters, noting that the basic blood diagnostics sector has not had a significant advance in technology in 90 years.

Walgreens Boots Alliance terminated its relationship with the company last month and closed operations at all 40 Theranos Wellness Centers at its drug stores in Arizona.

Theranos is also facing a class action lawsuit filed in May accusing it of endangering customer health through "massive failures" that misrepresented test results.

The Palo Alto, California-based company is also being investigated by other federal and state agencies, including the U.S. Securities and Exchange Commission and the State Department of Health in Arizona.

Theranos Inc founder and CEO Elizabeth Holmes, once touted as the Steve Jobs of biotech for her company's innovative blood-testing technology, has been barred by a U.S. regulator from owning or operating a lab for at least two years.

Dealing the biggest blow yet to the privately held company, the Centers for Medicare & Medicaid Services revoked a key certificate for its California lab and terminated the facility's approval to receive government payments.

Medicare is the government's medical insurance program for the elderly, while Medicaid is for the poor.

The sanctions, which also include an unspecified monetary penalty, come six months after the regulator sent a scathing letter to the company, saying its practices were jeopardizing patient health and safety.

Theranos said late on Thursday that it would continue to service its customers through its Arizona lab.

The company, once valued at $9 billion, was founded by Holmes in 2003 to develop an innovative blood testing device that would give quicker results using just one drop of blood.

However, its fortunes waned after the Wall Street Journal published a series of articles starting in October last year that suggested the devices were flawed and inaccurate.

Forbes magazine said last month that the company's value had fallen to about $800 million, while Holmes' own net worth had shrunk to zero from about $4.5 billion - a figure the magazine had said had made her the richest self-made woman in America.

"Everyone wanted her to succeed," Steve Brozak, president of WBB Securities, told Reuters, noting that the basic blood diagnostics sector has not had a significant advance in technology in 90 years.

Walgreens Boots Alliance terminated its relationship with the company last month and closed operations at all 40 Theranos Wellness Centers at its drug stores in Arizona.

Theranos is also facing a class action lawsuit filed in May accusing it of endangering customer health through "massive failures" that misrepresented test results.

The Palo Alto, California-based company is also being investigated by other federal and state agencies, including the U.S. Securities and Exchange Commission and the State Department of Health in Arizona.

As physicians, we have a responsibility to stay abreast of the medical literature to provide state of the art pediatric care. We have at our disposal reliable resources to stay current, from professional organizations that provide us with updated practice guidelines, to scientific publications with cutting-edge medical research and clinical databases that offer support for medical decision making.

The greater public, however, does not have the luxury of a guide to navigate the health information ocean. In addition to traditional news outlets, such as television and the printed press, the advent of the Internet and social media have placed unprecedented amounts of medical information at everyone’s fingertips.¹ But not all health information is created equal, and even “Dr. Google” has admitted its symptoms search engine has not been very helpful.²

Many websites, despite authoritarian-sounding domain names, are not impartial providers of medical information. The power of the media to shape public perception is perhaps nowhere more poignantly felt than in the pediatric community, where the now thoroughly debunked study by Dr. Andrew Wakefield that linked the MMR vaccine to autism continues to have lingering effects on vaccination rates.^3,4

I recently completed an internship in medical journalism with ABC News in New York City to better understand how the news media provides health and medical information to millions of Americans. Lay medical journalists have the complicated task of reviewing new research, weighing its newsworthiness, and distilling complex concepts down to easy-to-digest sound bites. Working with medical correspondents and the editorial team, I reviewed new scientific studies, dissected their impact, and pondered their potential for a catchy headline. I also wrote content for medical segments and participated in educational Twitter chats. What made the headlines wasn’t always what I thought should make the headlines, and translating the results of a randomized, controlled trial into a 60-second script for television felt near impossible. Dipping my toes into medical journalism gave me a new appreciation of my role as a physician educator – avoiding health information overload and promoting meaningful health literacy for my patients.

© Catherine Yeulet/ iStockphoto

The 24/7 medical news cycle is here to stay. Our patients will continue to use various media platforms for medical information whether we like it or not. It is our responsibility as pediatricians to help families get the most relevant and current medical information. By directing them to trustworthy sources, such as the American Academy of Pediatrics ^at healthychildren.org or the National Library of Medicine at www.nlm.nih.gov/medlineplus, we can strengthen our therapeutic alliance while promoting health literacy.

References

1. Interact J Med Res. 2015 Jun 22;4(2):e12.

2. “Google Sharpens Search Results for ‘Skin Rash,’ ‘Tummy Ache’ and Other Symptoms,” Wall Street Journal, by Nathan Olivarez-Giles, June 20, 2016.

3. “A Discredited Vaccine Study’s Continuing Impact on Public Health,” by Clyde Haberman, Feb. 1, 2015.

4. Ann Pharmacother. 2011 Oct;45(10):1302-4.

Dr. Talbot is a third-year resident at Monroe Carell Jr. Children’s Hospital at Vanderbilt in Nashville, Tenn. She said she had no relevant financial disclosures. Email her at [email protected].

As physicians, we have a responsibility to stay abreast of the medical literature to provide state of the art pediatric care. We have at our disposal reliable resources to stay current, from professional organizations that provide us with updated practice guidelines, to scientific publications with cutting-edge medical research and clinical databases that offer support for medical decision making.

The greater public, however, does not have the luxury of a guide to navigate the health information ocean. In addition to traditional news outlets, such as television and the printed press, the advent of the Internet and social media have placed unprecedented amounts of medical information at everyone’s fingertips.¹ But not all health information is created equal, and even “Dr. Google” has admitted its symptoms search engine has not been very helpful.²

Many websites, despite authoritarian-sounding domain names, are not impartial providers of medical information. The power of the media to shape public perception is perhaps nowhere more poignantly felt than in the pediatric community, where the now thoroughly debunked study by Dr. Andrew Wakefield that linked the MMR vaccine to autism continues to have lingering effects on vaccination rates.^3,4

I recently completed an internship in medical journalism with ABC News in New York City to better understand how the news media provides health and medical information to millions of Americans. Lay medical journalists have the complicated task of reviewing new research, weighing its newsworthiness, and distilling complex concepts down to easy-to-digest sound bites. Working with medical correspondents and the editorial team, I reviewed new scientific studies, dissected their impact, and pondered their potential for a catchy headline. I also wrote content for medical segments and participated in educational Twitter chats. What made the headlines wasn’t always what I thought should make the headlines, and translating the results of a randomized, controlled trial into a 60-second script for television felt near impossible. Dipping my toes into medical journalism gave me a new appreciation of my role as a physician educator – avoiding health information overload and promoting meaningful health literacy for my patients.

© Catherine Yeulet/ iStockphoto

The 24/7 medical news cycle is here to stay. Our patients will continue to use various media platforms for medical information whether we like it or not. It is our responsibility as pediatricians to help families get the most relevant and current medical information. By directing them to trustworthy sources, such as the American Academy of Pediatrics ^at healthychildren.org or the National Library of Medicine at www.nlm.nih.gov/medlineplus, we can strengthen our therapeutic alliance while promoting health literacy.

References

1. Interact J Med Res. 2015 Jun 22;4(2):e12.

2. “Google Sharpens Search Results for ‘Skin Rash,’ ‘Tummy Ache’ and Other Symptoms,” Wall Street Journal, by Nathan Olivarez-Giles, June 20, 2016.

3. “A Discredited Vaccine Study’s Continuing Impact on Public Health,” by Clyde Haberman, Feb. 1, 2015.

4. Ann Pharmacother. 2011 Oct;45(10):1302-4.

Dr. Talbot is a third-year resident at Monroe Carell Jr. Children’s Hospital at Vanderbilt in Nashville, Tenn. She said she had no relevant financial disclosures. Email her at [email protected].

As physicians, we have a responsibility to stay abreast of the medical literature to provide state of the art pediatric care. We have at our disposal reliable resources to stay current, from professional organizations that provide us with updated practice guidelines, to scientific publications with cutting-edge medical research and clinical databases that offer support for medical decision making.

The greater public, however, does not have the luxury of a guide to navigate the health information ocean. In addition to traditional news outlets, such as television and the printed press, the advent of the Internet and social media have placed unprecedented amounts of medical information at everyone’s fingertips.¹ But not all health information is created equal, and even “Dr. Google” has admitted its symptoms search engine has not been very helpful.²

Many websites, despite authoritarian-sounding domain names, are not impartial providers of medical information. The power of the media to shape public perception is perhaps nowhere more poignantly felt than in the pediatric community, where the now thoroughly debunked study by Dr. Andrew Wakefield that linked the MMR vaccine to autism continues to have lingering effects on vaccination rates.^3,4

I recently completed an internship in medical journalism with ABC News in New York City to better understand how the news media provides health and medical information to millions of Americans. Lay medical journalists have the complicated task of reviewing new research, weighing its newsworthiness, and distilling complex concepts down to easy-to-digest sound bites. Working with medical correspondents and the editorial team, I reviewed new scientific studies, dissected their impact, and pondered their potential for a catchy headline. I also wrote content for medical segments and participated in educational Twitter chats. What made the headlines wasn’t always what I thought should make the headlines, and translating the results of a randomized, controlled trial into a 60-second script for television felt near impossible. Dipping my toes into medical journalism gave me a new appreciation of my role as a physician educator – avoiding health information overload and promoting meaningful health literacy for my patients.

© Catherine Yeulet/ iStockphoto

The 24/7 medical news cycle is here to stay. Our patients will continue to use various media platforms for medical information whether we like it or not. It is our responsibility as pediatricians to help families get the most relevant and current medical information. By directing them to trustworthy sources, such as the American Academy of Pediatrics ^at healthychildren.org or the National Library of Medicine at www.nlm.nih.gov/medlineplus, we can strengthen our therapeutic alliance while promoting health literacy.

References

1. Interact J Med Res. 2015 Jun 22;4(2):e12.

2. “Google Sharpens Search Results for ‘Skin Rash,’ ‘Tummy Ache’ and Other Symptoms,” Wall Street Journal, by Nathan Olivarez-Giles, June 20, 2016.

3. “A Discredited Vaccine Study’s Continuing Impact on Public Health,” by Clyde Haberman, Feb. 1, 2015.

4. Ann Pharmacother. 2011 Oct;45(10):1302-4.

Dr. Talbot is a third-year resident at Monroe Carell Jr. Children’s Hospital at Vanderbilt in Nashville, Tenn. She said she had no relevant financial disclosures. Email her at [email protected].

A U.S. Supreme Court ruling that expands liability under the federal False Claims Act (FCA) could have both positive and negative implications for physicians accused of submitting false claims to the government.

Justices ruled June 16 that health care providers can be held liable under the FCA if they bill for a service, but fail to comply with underlying regulations, even if the violation is not explicit in the claim. The decision upholds use of the “implied false certification theory” in FCA cases, which provides that any submission for government payment include an implicit certification of compliance with all applicable contract requirements, laws, and regulations.

The ruling allows a lawsuit by a patient’s family to continue against Universal Health Services, a national hospital management company. The plaintiff, Julio Escobar, claims that Universal presented false claims to Medicaid by seeking payments for services provided by unlicensed, unsupervised health care providers. Although the reimbursement claims submitted to the government accurately described the services provided and cited the correct charges, the plaintiffs alleged that because the clinic’s operations violated state requirements to participate in Medicaid, Universal had also violated the FCA. Universal argued the FCA suit was invalid because a reimbursement claim cannot be false unless its details are untrue or inaccurate.

The Supreme Court ruled in favor of the plaintiffs. By using National Provider Identification numbers that corresponded to specific job titles without disclosing many violations of staff and licensing requirements, Universal’s claims constituted misrepresentations, the justices said.

The opinion includes language that is both helpful and harmful to physicians, according to health law attorneys. On the one hand, the justices supported the implied certification theory, thus expanding the scope of potential liability under the FCA in certain circumstances, said George B. Breen, a Washington-based health law attorney.

“The court’s decision is significant for health care providers and suppliers that submit claims to federally funded health care programs, including Medicare and Medicaid, because the FCA remains one of the federal government’s primary enforcement tools,” Mr. Breen said in an interview. “In the court’s view, half-truths in a claim for reimbursement from a government program … [are] just as actionable as an outright lie if the failure to disclose noncompliance with a statute, regulation, or contract term makes those representations misleading half-truths.”

However, the Supreme Court rejected the government’s notion that every omission, regulatory violation, or contract breach can result in fines and damages under the FCA. The compliance violation must be material to the government’s payment decision, the justices said. This means an alleged regulatory or contractual violation must have mattered to the agency’s payment decision to be actionable under the FCA, said David L. Douglass, a Washington-based health law attorney.

In their written opinion, the justices offered this example: If the government adds a requirement that health providers who participate in Medicaid must buy American-made staplers, and a health provider submits a claim but fails to disclose the use of foreign staplers, that provider should not be held liable under the FCA.

“An undisclosed fact is material if, for instance, no one can say with reason that the plaintiff would have signed this contract if informed of the likelihood of the undisclosed fact,” the justices wrote. “A misrepresentation cannot be deemed material merely because the government designates compliance with a particular requirement as a condition of payment. … The False Claims Act does not adopt such an extraordinarily expansive view of liability.”

This aspect of the ruling is good news for defendants and potential FCA targets, Mr. Douglass said in an interview.

“The court has restored the role of the materiality element,” he said. “The materiality element is a stringent protection against the risk that technical instances of noncompliance can become the basis for punitive liability.”

The high court also noted that if the underlying violation is known to widely occur and, nonetheless, Medicare regularly pays such claims, the violation is likely not material to payment, added William W. Horton, a Birmingham, Ala.–based health law attorney and chair of the American Bar Association Health Law Section.

“What I think this does, from the standpoint of defense of these claims, is open up new possibilities for arguing about whether a technical violation of a legal requirement, in fact, satisfies this test,” Mr. Horton said in an interview. “Whether, if CMS had known the violation occurred, would that have been material to CMS’s decision to pay the claim or not?”

But attorneys for plaintiffs and whistle-blowers are also hailing the Supreme Court opinion as positive for their clients.

Stephen M. Kohn, executive director of the National Whistleblower Center, said the Supreme Court correctly ruled on the issue.

“The legal position taken by the Chamber of Commerce and health care industry in this case was dumbfounding,” Mr. Kohn said in a statement. “Had the court agreed with the chamber and its allies – that you can bill the taxpayers for the services of a so-called doctor who was in fact unlicensed, and whose degree came from an unaccredited Internet college – then the floodgates would be opened for fraud in government contracting.”

Houston-based plaintiffs’ attorney Joel Androphy, who represents whistle-blowers, called the opinion “very favorable” for implied certification claims.

“Eliminating barriers such as the mandated condition of payment language in statutes or regulations was a proper change in direction for evaluating pleadings,” Mr. Androphy said in an interview. “If the defendant cheats, there should not be a free pass because Congress did not include magic wording in statute or regulation to support a false claims case. Materiality may be a lingering area of dispute; however the court made clear that a commonsense approach should be applied.”

[email protected]

On Twitter @legal_med

A U.S. Supreme Court ruling that expands liability under the federal False Claims Act (FCA) could have both positive and negative implications for physicians accused of submitting false claims to the government.

Justices ruled June 16 that health care providers can be held liable under the FCA if they bill for a service, but fail to comply with underlying regulations, even if the violation is not explicit in the claim. The decision upholds use of the “implied false certification theory” in FCA cases, which provides that any submission for government payment include an implicit certification of compliance with all applicable contract requirements, laws, and regulations.

The ruling allows a lawsuit by a patient’s family to continue against Universal Health Services, a national hospital management company. The plaintiff, Julio Escobar, claims that Universal presented false claims to Medicaid by seeking payments for services provided by unlicensed, unsupervised health care providers. Although the reimbursement claims submitted to the government accurately described the services provided and cited the correct charges, the plaintiffs alleged that because the clinic’s operations violated state requirements to participate in Medicaid, Universal had also violated the FCA. Universal argued the FCA suit was invalid because a reimbursement claim cannot be false unless its details are untrue or inaccurate.

The Supreme Court ruled in favor of the plaintiffs. By using National Provider Identification numbers that corresponded to specific job titles without disclosing many violations of staff and licensing requirements, Universal’s claims constituted misrepresentations, the justices said.

The opinion includes language that is both helpful and harmful to physicians, according to health law attorneys. On the one hand, the justices supported the implied certification theory, thus expanding the scope of potential liability under the FCA in certain circumstances, said George B. Breen, a Washington-based health law attorney.

“The court’s decision is significant for health care providers and suppliers that submit claims to federally funded health care programs, including Medicare and Medicaid, because the FCA remains one of the federal government’s primary enforcement tools,” Mr. Breen said in an interview. “In the court’s view, half-truths in a claim for reimbursement from a government program … [are] just as actionable as an outright lie if the failure to disclose noncompliance with a statute, regulation, or contract term makes those representations misleading half-truths.”

However, the Supreme Court rejected the government’s notion that every omission, regulatory violation, or contract breach can result in fines and damages under the FCA. The compliance violation must be material to the government’s payment decision, the justices said. This means an alleged regulatory or contractual violation must have mattered to the agency’s payment decision to be actionable under the FCA, said David L. Douglass, a Washington-based health law attorney.

In their written opinion, the justices offered this example: If the government adds a requirement that health providers who participate in Medicaid must buy American-made staplers, and a health provider submits a claim but fails to disclose the use of foreign staplers, that provider should not be held liable under the FCA.

“An undisclosed fact is material if, for instance, no one can say with reason that the plaintiff would have signed this contract if informed of the likelihood of the undisclosed fact,” the justices wrote. “A misrepresentation cannot be deemed material merely because the government designates compliance with a particular requirement as a condition of payment. … The False Claims Act does not adopt such an extraordinarily expansive view of liability.”

This aspect of the ruling is good news for defendants and potential FCA targets, Mr. Douglass said in an interview.

“The court has restored the role of the materiality element,” he said. “The materiality element is a stringent protection against the risk that technical instances of noncompliance can become the basis for punitive liability.”

The high court also noted that if the underlying violation is known to widely occur and, nonetheless, Medicare regularly pays such claims, the violation is likely not material to payment, added William W. Horton, a Birmingham, Ala.–based health law attorney and chair of the American Bar Association Health Law Section.

“What I think this does, from the standpoint of defense of these claims, is open up new possibilities for arguing about whether a technical violation of a legal requirement, in fact, satisfies this test,” Mr. Horton said in an interview. “Whether, if CMS had known the violation occurred, would that have been material to CMS’s decision to pay the claim or not?”

But attorneys for plaintiffs and whistle-blowers are also hailing the Supreme Court opinion as positive for their clients.

Stephen M. Kohn, executive director of the National Whistleblower Center, said the Supreme Court correctly ruled on the issue.

“The legal position taken by the Chamber of Commerce and health care industry in this case was dumbfounding,” Mr. Kohn said in a statement. “Had the court agreed with the chamber and its allies – that you can bill the taxpayers for the services of a so-called doctor who was in fact unlicensed, and whose degree came from an unaccredited Internet college – then the floodgates would be opened for fraud in government contracting.”

Houston-based plaintiffs’ attorney Joel Androphy, who represents whistle-blowers, called the opinion “very favorable” for implied certification claims.

“Eliminating barriers such as the mandated condition of payment language in statutes or regulations was a proper change in direction for evaluating pleadings,” Mr. Androphy said in an interview. “If the defendant cheats, there should not be a free pass because Congress did not include magic wording in statute or regulation to support a false claims case. Materiality may be a lingering area of dispute; however the court made clear that a commonsense approach should be applied.”

[email protected]

On Twitter @legal_med

A U.S. Supreme Court ruling that expands liability under the federal False Claims Act (FCA) could have both positive and negative implications for physicians accused of submitting false claims to the government.

Justices ruled June 16 that health care providers can be held liable under the FCA if they bill for a service, but fail to comply with underlying regulations, even if the violation is not explicit in the claim. The decision upholds use of the “implied false certification theory” in FCA cases, which provides that any submission for government payment include an implicit certification of compliance with all applicable contract requirements, laws, and regulations.

The ruling allows a lawsuit by a patient’s family to continue against Universal Health Services, a national hospital management company. The plaintiff, Julio Escobar, claims that Universal presented false claims to Medicaid by seeking payments for services provided by unlicensed, unsupervised health care providers. Although the reimbursement claims submitted to the government accurately described the services provided and cited the correct charges, the plaintiffs alleged that because the clinic’s operations violated state requirements to participate in Medicaid, Universal had also violated the FCA. Universal argued the FCA suit was invalid because a reimbursement claim cannot be false unless its details are untrue or inaccurate.

The Supreme Court ruled in favor of the plaintiffs. By using National Provider Identification numbers that corresponded to specific job titles without disclosing many violations of staff and licensing requirements, Universal’s claims constituted misrepresentations, the justices said.

The opinion includes language that is both helpful and harmful to physicians, according to health law attorneys. On the one hand, the justices supported the implied certification theory, thus expanding the scope of potential liability under the FCA in certain circumstances, said George B. Breen, a Washington-based health law attorney.

“The court’s decision is significant for health care providers and suppliers that submit claims to federally funded health care programs, including Medicare and Medicaid, because the FCA remains one of the federal government’s primary enforcement tools,” Mr. Breen said in an interview. “In the court’s view, half-truths in a claim for reimbursement from a government program … [are] just as actionable as an outright lie if the failure to disclose noncompliance with a statute, regulation, or contract term makes those representations misleading half-truths.”

However, the Supreme Court rejected the government’s notion that every omission, regulatory violation, or contract breach can result in fines and damages under the FCA. The compliance violation must be material to the government’s payment decision, the justices said. This means an alleged regulatory or contractual violation must have mattered to the agency’s payment decision to be actionable under the FCA, said David L. Douglass, a Washington-based health law attorney.

In their written opinion, the justices offered this example: If the government adds a requirement that health providers who participate in Medicaid must buy American-made staplers, and a health provider submits a claim but fails to disclose the use of foreign staplers, that provider should not be held liable under the FCA.

“An undisclosed fact is material if, for instance, no one can say with reason that the plaintiff would have signed this contract if informed of the likelihood of the undisclosed fact,” the justices wrote. “A misrepresentation cannot be deemed material merely because the government designates compliance with a particular requirement as a condition of payment. … The False Claims Act does not adopt such an extraordinarily expansive view of liability.”

This aspect of the ruling is good news for defendants and potential FCA targets, Mr. Douglass said in an interview.

“The court has restored the role of the materiality element,” he said. “The materiality element is a stringent protection against the risk that technical instances of noncompliance can become the basis for punitive liability.”

The high court also noted that if the underlying violation is known to widely occur and, nonetheless, Medicare regularly pays such claims, the violation is likely not material to payment, added William W. Horton, a Birmingham, Ala.–based health law attorney and chair of the American Bar Association Health Law Section.

“What I think this does, from the standpoint of defense of these claims, is open up new possibilities for arguing about whether a technical violation of a legal requirement, in fact, satisfies this test,” Mr. Horton said in an interview. “Whether, if CMS had known the violation occurred, would that have been material to CMS’s decision to pay the claim or not?”

But attorneys for plaintiffs and whistle-blowers are also hailing the Supreme Court opinion as positive for their clients.

Stephen M. Kohn, executive director of the National Whistleblower Center, said the Supreme Court correctly ruled on the issue.

“The legal position taken by the Chamber of Commerce and health care industry in this case was dumbfounding,” Mr. Kohn said in a statement. “Had the court agreed with the chamber and its allies – that you can bill the taxpayers for the services of a so-called doctor who was in fact unlicensed, and whose degree came from an unaccredited Internet college – then the floodgates would be opened for fraud in government contracting.”

Houston-based plaintiffs’ attorney Joel Androphy, who represents whistle-blowers, called the opinion “very favorable” for implied certification claims.

“Eliminating barriers such as the mandated condition of payment language in statutes or regulations was a proper change in direction for evaluating pleadings,” Mr. Androphy said in an interview. “If the defendant cheats, there should not be a free pass because Congress did not include magic wording in statute or regulation to support a false claims case. Materiality may be a lingering area of dispute; however the court made clear that a commonsense approach should be applied.”

[email protected]

On Twitter @legal_med

In Congressional testimony, VA officials frequently tout studies that indicate that the VA delivers high-quality health care that meets or exceeds the care delivered at private facilities. These studies often stand in sharp contrast to the criticism leveled at the VA and news stories of health care discrepancies. However, a new meta-analysis of studies on quality at VA facilities suggests that the VA health care system generally performs better than or similar to other health care systems for providing safe and effective care to patients.

The study, published in the Journal of General Internal Medicine and conducted by RAND Corporation researcher Courtney Gidengil , MD, MPH, found 69 articles on VA quality across dimensions, including safety and effectiveness. According to Dr. Gidengil, 22 of 34 safety studies and 20 of 24 studies that focused on effectiveness showed that VA facilities provided the same, if not better, quality of care as do private facilities. These studies focused on safety measures, preventive medicine best practices. In the studies, surgical patients in the VA system and VA nursing homes patients had death rates similar to patients in other health systems.

“We found that the overall quality of care in the VA health system compares favorably to other segments of the U.S. health care system,” said Dr. Gidengil. “In some areas, the quality of care provided by the VA exceeded what we found in other settings, although there were areas where the quality of VA care fell short.”

The study updated and expanded on a similar study conducted in 2009. In addressing timeliness, equity, efficiency, and patient-centeredness, there was too little data to draw reliable conclusions. Similarly, studies on the availability of services had mixed results. During the past 5 years, the study was not able to find any trends indicating whether the VA was superior or inferior compared with other health settings.

“Comparing the VA to other health care settings can be difficult because the VA has a patient population that is different from most other settings, with patients who may be sicker,” Gidengil said. “But it's important to do more of this work in the future so we can better understand the quality of care the VA provides.”

Support for the study was provided by the VA.

In Congressional testimony, VA officials frequently tout studies that indicate that the VA delivers high-quality health care that meets or exceeds the care delivered at private facilities. These studies often stand in sharp contrast to the criticism leveled at the VA and news stories of health care discrepancies. However, a new meta-analysis of studies on quality at VA facilities suggests that the VA health care system generally performs better than or similar to other health care systems for providing safe and effective care to patients.

The study, published in the Journal of General Internal Medicine and conducted by RAND Corporation researcher Courtney Gidengil , MD, MPH, found 69 articles on VA quality across dimensions, including safety and effectiveness. According to Dr. Gidengil, 22 of 34 safety studies and 20 of 24 studies that focused on effectiveness showed that VA facilities provided the same, if not better, quality of care as do private facilities. These studies focused on safety measures, preventive medicine best practices. In the studies, surgical patients in the VA system and VA nursing homes patients had death rates similar to patients in other health systems.

“We found that the overall quality of care in the VA health system compares favorably to other segments of the U.S. health care system,” said Dr. Gidengil. “In some areas, the quality of care provided by the VA exceeded what we found in other settings, although there were areas where the quality of VA care fell short.”

The study updated and expanded on a similar study conducted in 2009. In addressing timeliness, equity, efficiency, and patient-centeredness, there was too little data to draw reliable conclusions. Similarly, studies on the availability of services had mixed results. During the past 5 years, the study was not able to find any trends indicating whether the VA was superior or inferior compared with other health settings.

“Comparing the VA to other health care settings can be difficult because the VA has a patient population that is different from most other settings, with patients who may be sicker,” Gidengil said. “But it's important to do more of this work in the future so we can better understand the quality of care the VA provides.”

Support for the study was provided by the VA.

In Congressional testimony, VA officials frequently tout studies that indicate that the VA delivers high-quality health care that meets or exceeds the care delivered at private facilities. These studies often stand in sharp contrast to the criticism leveled at the VA and news stories of health care discrepancies. However, a new meta-analysis of studies on quality at VA facilities suggests that the VA health care system generally performs better than or similar to other health care systems for providing safe and effective care to patients.

The study, published in the Journal of General Internal Medicine and conducted by RAND Corporation researcher Courtney Gidengil , MD, MPH, found 69 articles on VA quality across dimensions, including safety and effectiveness. According to Dr. Gidengil, 22 of 34 safety studies and 20 of 24 studies that focused on effectiveness showed that VA facilities provided the same, if not better, quality of care as do private facilities. These studies focused on safety measures, preventive medicine best practices. In the studies, surgical patients in the VA system and VA nursing homes patients had death rates similar to patients in other health systems.

“We found that the overall quality of care in the VA health system compares favorably to other segments of the U.S. health care system,” said Dr. Gidengil. “In some areas, the quality of care provided by the VA exceeded what we found in other settings, although there were areas where the quality of VA care fell short.”

The study updated and expanded on a similar study conducted in 2009. In addressing timeliness, equity, efficiency, and patient-centeredness, there was too little data to draw reliable conclusions. Similarly, studies on the availability of services had mixed results. During the past 5 years, the study was not able to find any trends indicating whether the VA was superior or inferior compared with other health settings.

“Comparing the VA to other health care settings can be difficult because the VA has a patient population that is different from most other settings, with patients who may be sicker,” Gidengil said. “But it's important to do more of this work in the future so we can better understand the quality of care the VA provides.”

Support for the study was provided by the VA.

“The liver, not the spleen, is the major on-demand site of red blood cell elimination and iron recycling,” according to Filip Swirski, PhD, of the Massachusetts General Hospital Center for Systems Biology, and his colleagues.

The liver relies on a buffer system consisting of bone marrow–derived monocytes that consume damaged red blood cells (RBCs) in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling, the researchers concluded in a study published in Nature Medicine.

© pavlen/iStockphoto

The study was designed to examine how the body clears old and damaged RBCs without releasing toxic levels of free iron. Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury and can lead to anemia.

The researchers used several different models of RBC damage to examine RBC clearance and iron recycling in a mouse model. Damaged RBCs in the bloodstream prompted an increase in monocytes that took up the damaged cells and traveled to both the liver and the spleen. Within hours, almost all of the damaged RBCs were located within specialized macrophages seen only in the liver. Chemokines drew the monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1–expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4^neg macrophages are transient, reside alongside embryonically derived T-cell immunoglobulin and mucin domain containing 4^high Kupffer cells, and depend on the growth factor Csf1 and the transcription factor Nrf2, the researchers wrote.

Blocking that process resulted in impaired RBC clearance, toxic levels of free iron and hemoglobin, and signs of liver and kidney damage.

“If overactive, (the mechanism) could remove too many RBCs, but if (the mechanism is) sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions,” Dr. Swirski said in a press release.

The researchers had no financial conflicts of interest. The study was funded by the National Institutes of Health.

[email protected]

On Twitter @maryjodales

“The liver, not the spleen, is the major on-demand site of red blood cell elimination and iron recycling,” according to Filip Swirski, PhD, of the Massachusetts General Hospital Center for Systems Biology, and his colleagues.

The liver relies on a buffer system consisting of bone marrow–derived monocytes that consume damaged red blood cells (RBCs) in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling, the researchers concluded in a study published in Nature Medicine.

© pavlen/iStockphoto

The study was designed to examine how the body clears old and damaged RBCs without releasing toxic levels of free iron. Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury and can lead to anemia.

The researchers used several different models of RBC damage to examine RBC clearance and iron recycling in a mouse model. Damaged RBCs in the bloodstream prompted an increase in monocytes that took up the damaged cells and traveled to both the liver and the spleen. Within hours, almost all of the damaged RBCs were located within specialized macrophages seen only in the liver. Chemokines drew the monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1–expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4^neg macrophages are transient, reside alongside embryonically derived T-cell immunoglobulin and mucin domain containing 4^high Kupffer cells, and depend on the growth factor Csf1 and the transcription factor Nrf2, the researchers wrote.

Blocking that process resulted in impaired RBC clearance, toxic levels of free iron and hemoglobin, and signs of liver and kidney damage.

“If overactive, (the mechanism) could remove too many RBCs, but if (the mechanism is) sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions,” Dr. Swirski said in a press release.

The researchers had no financial conflicts of interest. The study was funded by the National Institutes of Health.

[email protected]

On Twitter @maryjodales

“The liver, not the spleen, is the major on-demand site of red blood cell elimination and iron recycling,” according to Filip Swirski, PhD, of the Massachusetts General Hospital Center for Systems Biology, and his colleagues.

The liver relies on a buffer system consisting of bone marrow–derived monocytes that consume damaged red blood cells (RBCs) in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling, the researchers concluded in a study published in Nature Medicine.

© pavlen/iStockphoto

The study was designed to examine how the body clears old and damaged RBCs without releasing toxic levels of free iron. Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury and can lead to anemia.

The researchers used several different models of RBC damage to examine RBC clearance and iron recycling in a mouse model. Damaged RBCs in the bloodstream prompted an increase in monocytes that took up the damaged cells and traveled to both the liver and the spleen. Within hours, almost all of the damaged RBCs were located within specialized macrophages seen only in the liver. Chemokines drew the monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1–expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4^neg macrophages are transient, reside alongside embryonically derived T-cell immunoglobulin and mucin domain containing 4^high Kupffer cells, and depend on the growth factor Csf1 and the transcription factor Nrf2, the researchers wrote.

Blocking that process resulted in impaired RBC clearance, toxic levels of free iron and hemoglobin, and signs of liver and kidney damage.

“If overactive, (the mechanism) could remove too many RBCs, but if (the mechanism is) sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions,” Dr. Swirski said in a press release.

The researchers had no financial conflicts of interest. The study was funded by the National Institutes of Health.

[email protected]

On Twitter @maryjodales

We are pleased to announce that Gary Goldenberg, MD, has been named Digital Editor of Cutis. In this new role, Dr. Goldenberg will work closely with our Editorial Board and editorial/publishing staff on our website, www.cutis.com. Dr. Goldenberg is Assistant Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, New York, and Medical Director of the Dermatology Faculty Practice at The Mount Sinai Medical Center, New York. Dr. Goldenberg has been a member of the Cutis Editorial Board since April 2008 due to his expertise in dermatopathology as well as medical and cosmetic dermatology. Over the years, Dr. Goldenberg’s involvement in the journal’s presence in print and online has expanded to include a regular series of Cosmetic Dermatology articles and video commentaries on practice management topics. With Dr. Goldenberg’s oversight, we will expand our offerings of highly practical content in the digital arena with an emphasis on resources for the practicing dermatologist.

“We welcome Gary as our first Digital Editor of Cutis and thank him for agreeing to lead us into the future,” said Cutis Editor-in-Chief Vincent A. DeLeo, MD. “Cutis has been a leader in print readership among dermatologists and with Gary’s input, we will be able to offer more to our readers online.”

We are pleased to announce that Gary Goldenberg, MD, has been named Digital Editor of Cutis. In this new role, Dr. Goldenberg will work closely with our Editorial Board and editorial/publishing staff on our website, www.cutis.com. Dr. Goldenberg is Assistant Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, New York, and Medical Director of the Dermatology Faculty Practice at The Mount Sinai Medical Center, New York. Dr. Goldenberg has been a member of the Cutis Editorial Board since April 2008 due to his expertise in dermatopathology as well as medical and cosmetic dermatology. Over the years, Dr. Goldenberg’s involvement in the journal’s presence in print and online has expanded to include a regular series of Cosmetic Dermatology articles and video commentaries on practice management topics. With Dr. Goldenberg’s oversight, we will expand our offerings of highly practical content in the digital arena with an emphasis on resources for the practicing dermatologist.

“We welcome Gary as our first Digital Editor of Cutis and thank him for agreeing to lead us into the future,” said Cutis Editor-in-Chief Vincent A. DeLeo, MD. “Cutis has been a leader in print readership among dermatologists and with Gary’s input, we will be able to offer more to our readers online.”

We are pleased to announce that Gary Goldenberg, MD, has been named Digital Editor of Cutis. In this new role, Dr. Goldenberg will work closely with our Editorial Board and editorial/publishing staff on our website, www.cutis.com. Dr. Goldenberg is Assistant Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, New York, and Medical Director of the Dermatology Faculty Practice at The Mount Sinai Medical Center, New York. Dr. Goldenberg has been a member of the Cutis Editorial Board since April 2008 due to his expertise in dermatopathology as well as medical and cosmetic dermatology. Over the years, Dr. Goldenberg’s involvement in the journal’s presence in print and online has expanded to include a regular series of Cosmetic Dermatology articles and video commentaries on practice management topics. With Dr. Goldenberg’s oversight, we will expand our offerings of highly practical content in the digital arena with an emphasis on resources for the practicing dermatologist.

“We welcome Gary as our first Digital Editor of Cutis and thank him for agreeing to lead us into the future,” said Cutis Editor-in-Chief Vincent A. DeLeo, MD. “Cutis has been a leader in print readership among dermatologists and with Gary’s input, we will be able to offer more to our readers online.”

Red blood cells

A new study contradicts previous beliefs about how the body disposes of red blood cells (RBCs) and recycles their iron.

The work suggests the accumulation and removal of aged or damaged RBCs largely takes place in the liver rather than the spleen, and the same is true for iron

recycling.

Researchers believe this discovery, published in Nature Medicine, could lead to improved treatment or prevention of anemia or iron toxicity.

“Textbooks tell us that red blood cells are eliminated in the spleen by specialized macrophages that live in that organ, but our study shows that the liver—not the spleen—is the major on-demand site of red blood cell elimination and iron recycling,” said study author Filip Swirski, PhD, of Massachusetts General Hospital in Boston.

“In addition to identifying the liver as the primary site of these processes, we also identified a transient population of bone-marrow-derived immune cells as the recycling cells.”

Dr Swirski and his colleagues used several different models of RBC damage to investigate the mechanisms involved in RBC clearance and the recycling of their iron.

Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes. These cells took up the damaged RBCs and traveled to both the liver and the spleen.

Several hours later, almost all of those RBCs were located within a population of specialized macrophages that were observed only in the liver. Those macrophages eventually disappeared once they were no longer needed.

The researchers also showed that expression of chemokines draws RBC-ingesting monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Blocking that process led to several indicators of impaired RBC clearance, including toxic levels of free iron and hemoglobin and signs of liver and kidney damage.

“The fact that the liver is the main organ of RBC removal and iron recycling is surprising, as is the fact that the liver relies on a buffer system consisting of bone marrow-derived monocytes that consume damaged red blood cells in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling,” Dr Swirski said.

“The mechanism we identified could be either helpful or damaging, depending on the conditions. If overactive, it could remove too many RBCs, but if it’s sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions.”

Red blood cells

A new study contradicts previous beliefs about how the body disposes of red blood cells (RBCs) and recycles their iron.

The work suggests the accumulation and removal of aged or damaged RBCs largely takes place in the liver rather than the spleen, and the same is true for iron

recycling.

Researchers believe this discovery, published in Nature Medicine, could lead to improved treatment or prevention of anemia or iron toxicity.

“Textbooks tell us that red blood cells are eliminated in the spleen by specialized macrophages that live in that organ, but our study shows that the liver—not the spleen—is the major on-demand site of red blood cell elimination and iron recycling,” said study author Filip Swirski, PhD, of Massachusetts General Hospital in Boston.

“In addition to identifying the liver as the primary site of these processes, we also identified a transient population of bone-marrow-derived immune cells as the recycling cells.”

Dr Swirski and his colleagues used several different models of RBC damage to investigate the mechanisms involved in RBC clearance and the recycling of their iron.

Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes. These cells took up the damaged RBCs and traveled to both the liver and the spleen.

Several hours later, almost all of those RBCs were located within a population of specialized macrophages that were observed only in the liver. Those macrophages eventually disappeared once they were no longer needed.

The researchers also showed that expression of chemokines draws RBC-ingesting monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Blocking that process led to several indicators of impaired RBC clearance, including toxic levels of free iron and hemoglobin and signs of liver and kidney damage.

“The fact that the liver is the main organ of RBC removal and iron recycling is surprising, as is the fact that the liver relies on a buffer system consisting of bone marrow-derived monocytes that consume damaged red blood cells in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling,” Dr Swirski said.

“The mechanism we identified could be either helpful or damaging, depending on the conditions. If overactive, it could remove too many RBCs, but if it’s sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions.”

Red blood cells

A new study contradicts previous beliefs about how the body disposes of red blood cells (RBCs) and recycles their iron.

The work suggests the accumulation and removal of aged or damaged RBCs largely takes place in the liver rather than the spleen, and the same is true for iron

recycling.

Researchers believe this discovery, published in Nature Medicine, could lead to improved treatment or prevention of anemia or iron toxicity.

“Textbooks tell us that red blood cells are eliminated in the spleen by specialized macrophages that live in that organ, but our study shows that the liver—not the spleen—is the major on-demand site of red blood cell elimination and iron recycling,” said study author Filip Swirski, PhD, of Massachusetts General Hospital in Boston.

“In addition to identifying the liver as the primary site of these processes, we also identified a transient population of bone-marrow-derived immune cells as the recycling cells.”

Dr Swirski and his colleagues used several different models of RBC damage to investigate the mechanisms involved in RBC clearance and the recycling of their iron.

Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes. These cells took up the damaged RBCs and traveled to both the liver and the spleen.

Several hours later, almost all of those RBCs were located within a population of specialized macrophages that were observed only in the liver. Those macrophages eventually disappeared once they were no longer needed.

The researchers also showed that expression of chemokines draws RBC-ingesting monocytes to the liver, resulting in the accumulation of the iron-recycling macrophages.

Blocking that process led to several indicators of impaired RBC clearance, including toxic levels of free iron and hemoglobin and signs of liver and kidney damage.

“The fact that the liver is the main organ of RBC removal and iron recycling is surprising, as is the fact that the liver relies on a buffer system consisting of bone marrow-derived monocytes that consume damaged red blood cells in the blood and settle in the liver, where they become the transient macrophages capable of iron recycling,” Dr Swirski said.

“The mechanism we identified could be either helpful or damaging, depending on the conditions. If overactive, it could remove too many RBCs, but if it’s sluggish or otherwise impaired, it could lead to iron toxicity. Further study could provide us with details of how this mechanism occurs in the first place and help us understand how to harness or suppress it in various conditions.”

Brentuximab vedotin (Adcetris)

Photo from Business Wire

Five-year follow-up data from a phase 2 trial indicate that a subset of Hodgkin lymphoma (HL) patients who fail autologous stem cell transplant can achieve long-term disease control with single-agent brentuximab vedotin and may potentially be cured.

Thirty-three percent of patients in this trial achieved a complete remission (CR) with brentuximab vedotin, 13% remained in CR for more than 5 years, and 9% remained in CR without receiving a consolidative allogeneic transplant.

These results were published in Blood. The trial was sponsored by Seattle Genetics, Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.

“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said study author Robert Chen, MD, of City of Hope National Medical Center in Duarte, California.

“The median survival of the patients on [brentuximab vedotin] monotherapy in this pivotal phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data.”

Dr Chen previously reported results from this trial at the 2010 ASH Annual Meeting.

The single-arm trial, which supported the US approval of brentuximab vedotin in 2011, was conducted in 102 patients with relapsed or refractory classical HL. The patients’ median age was 31 (range, 15-77), they had an ECOG status of 0 or 1, and both genders were represented equally.

The patients had received a median of 3.5 chemotherapy regimens (range, 1-13), 66% had received prior radiation, and all patients had received an autologous transplant. Seventy-one percent of patients were refractory to frontline therapy, and 42% were refractory to their most recent treatment.

The patients received brentuximab vedotin intravenously at 1.8 mg/kg every 21 days for a maximum of 16 cycles.

Results

Thirty-four patients (33%) achieved a CR. At the 5-year follow-up and end of the study, the median duration of response was not reached.

Thirteen of the 34 patients (38%) who achieved a CR remained in remission at study closure. Of these patients, 4 underwent consolidative allogeneic stem cell transplants while in remission, and 9 received no further therapy.

Among the patients who achieved a CR, the estimated 5-year overall survival (OS) rate was 64%, and the estimated 5-year progression-free survival (PFS) rate was 52%.

For the entire study cohort, the median OS was 40.5 months, and the median PFS was 9.3 months. The estimated 5-year OS was 41%, and the estimated 5-year PFS was 22%.

The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea.

Treatment-emergent peripheral neuropathy occurred in 56 patients (55%). Eighty-eight percent of these patients had an improvement in their symptoms, and 73% had complete resolution of peripheral neuropathy.

Brentuximab vedotin (Adcetris)

Photo from Business Wire

Five-year follow-up data from a phase 2 trial indicate that a subset of Hodgkin lymphoma (HL) patients who fail autologous stem cell transplant can achieve long-term disease control with single-agent brentuximab vedotin and may potentially be cured.

Thirty-three percent of patients in this trial achieved a complete remission (CR) with brentuximab vedotin, 13% remained in CR for more than 5 years, and 9% remained in CR without receiving a consolidative allogeneic transplant.

These results were published in Blood. The trial was sponsored by Seattle Genetics, Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.

“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said study author Robert Chen, MD, of City of Hope National Medical Center in Duarte, California.

“The median survival of the patients on [brentuximab vedotin] monotherapy in this pivotal phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data.”

Dr Chen previously reported results from this trial at the 2010 ASH Annual Meeting.

The single-arm trial, which supported the US approval of brentuximab vedotin in 2011, was conducted in 102 patients with relapsed or refractory classical HL. The patients’ median age was 31 (range, 15-77), they had an ECOG status of 0 or 1, and both genders were represented equally.

The patients had received a median of 3.5 chemotherapy regimens (range, 1-13), 66% had received prior radiation, and all patients had received an autologous transplant. Seventy-one percent of patients were refractory to frontline therapy, and 42% were refractory to their most recent treatment.

The patients received brentuximab vedotin intravenously at 1.8 mg/kg every 21 days for a maximum of 16 cycles.

Results

Thirty-four patients (33%) achieved a CR. At the 5-year follow-up and end of the study, the median duration of response was not reached.

Thirteen of the 34 patients (38%) who achieved a CR remained in remission at study closure. Of these patients, 4 underwent consolidative allogeneic stem cell transplants while in remission, and 9 received no further therapy.

Among the patients who achieved a CR, the estimated 5-year overall survival (OS) rate was 64%, and the estimated 5-year progression-free survival (PFS) rate was 52%.

For the entire study cohort, the median OS was 40.5 months, and the median PFS was 9.3 months. The estimated 5-year OS was 41%, and the estimated 5-year PFS was 22%.

The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea.

Treatment-emergent peripheral neuropathy occurred in 56 patients (55%). Eighty-eight percent of these patients had an improvement in their symptoms, and 73% had complete resolution of peripheral neuropathy.

Brentuximab vedotin (Adcetris)

Photo from Business Wire

Five-year follow-up data from a phase 2 trial indicate that a subset of Hodgkin lymphoma (HL) patients who fail autologous stem cell transplant can achieve long-term disease control with single-agent brentuximab vedotin and may potentially be cured.

Thirty-three percent of patients in this trial achieved a complete remission (CR) with brentuximab vedotin, 13% remained in CR for more than 5 years, and 9% remained in CR without receiving a consolidative allogeneic transplant.

These results were published in Blood. The trial was sponsored by Seattle Genetics, Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.

“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said study author Robert Chen, MD, of City of Hope National Medical Center in Duarte, California.

“The median survival of the patients on [brentuximab vedotin] monotherapy in this pivotal phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data.”

Dr Chen previously reported results from this trial at the 2010 ASH Annual Meeting.

The single-arm trial, which supported the US approval of brentuximab vedotin in 2011, was conducted in 102 patients with relapsed or refractory classical HL. The patients’ median age was 31 (range, 15-77), they had an ECOG status of 0 or 1, and both genders were represented equally.

The patients had received a median of 3.5 chemotherapy regimens (range, 1-13), 66% had received prior radiation, and all patients had received an autologous transplant. Seventy-one percent of patients were refractory to frontline therapy, and 42% were refractory to their most recent treatment.

The patients received brentuximab vedotin intravenously at 1.8 mg/kg every 21 days for a maximum of 16 cycles.

Results

Thirty-four patients (33%) achieved a CR. At the 5-year follow-up and end of the study, the median duration of response was not reached.

Thirteen of the 34 patients (38%) who achieved a CR remained in remission at study closure. Of these patients, 4 underwent consolidative allogeneic stem cell transplants while in remission, and 9 received no further therapy.

Among the patients who achieved a CR, the estimated 5-year overall survival (OS) rate was 64%, and the estimated 5-year progression-free survival (PFS) rate was 52%.

For the entire study cohort, the median OS was 40.5 months, and the median PFS was 9.3 months. The estimated 5-year OS was 41%, and the estimated 5-year PFS was 22%.

The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea.

Treatment-emergent peripheral neuropathy occurred in 56 patients (55%). Eighty-eight percent of these patients had an improvement in their symptoms, and 73% had complete resolution of peripheral neuropathy.